Studies on Serial Phlebotomy in Voluntary Blood Donors

描述(申请人提供)：沙利文在1981年首次提出，减少体内铁的储存可能会预防心血管疾病。众所周知，献血可以减少铁的储存，并在观察性研究中初步被认为与降低心血管风险有关，但解释这一发现的机制尚未得到很好的表征。我们的初步数据表明，与零星献血相比，高频献血与铁储存的严重减少、氧化应激的减少和血管内皮功能的改善有关。由于已知血管内皮功能的改善与心血管发病率和死亡率的降低有关，这些初步数据支持献血和降低心血管风险之间的潜在机制联系。我们现在建议进行一项前瞻性干预试验，以调查自愿献血者的献血和血管内皮功能之间的潜在联系机制。我们假设，连续静脉切开术与血管功能的改善有关，这些血管功能与除铁和除血的生理和生化效应有关。为了验证这一假设，目前因非医疗原因而推迟主动献血的150名铁质充足的自愿献血者将被随机分配到3个处理组：4次500毫升静脉采血术(6个月内不补充丢失的铁)、4次500毫升静脉采血术(6个月内静脉补充丢失的铁)或假采血术。这项三臂研究设计提供了区分失血和失铁对连续静脉切开术的生物学反应的相对贡献的方法。在基础状态和对一过性高同型半胱氨酸血症的反应中，将获得基础状态下肱动脉血流介导的扩张(血管内皮功能的非侵入性测量)、血和尿铁储存和氧化应激、红细胞和血浆容量、局部动脉壁切应力和红细胞生成素水平的指标。多变量混合效应模型将被用来确定研究治疗和血管功能之间的关联，以及铁和血液清除的生理和生化关联是否是这种关联的中介。这项研究将为铁储存和血管功能之间的关系提供新的见解，并将提供可能影响国家血液供应的献血对健康影响的新数据。超过50%的美国人一生中至少需要献血一次。我们提出了一项前瞻性随机双盲研究，以确定献血对血管功能的影响。该提案的总体目标是更好地描述献血对心血管健康的潜在影响。这项研究的发现将提供新的数据，这些数据可能会有利地影响美国的血液供应，并可能影响公共政策决策，如血色素沉着症(美国最常见的遗传病之一)筛查以及营养补充剂和食物中铁含量的监管。

DESCRIPTION (provided by applicant): Sullivan first proposed in 1981 that reduction in body iron stores may protect against cardiovascular disease. Blood donation is known to reduce iron stores and has been tentatively associated with reduced cardiovascular risk in observational studies, but the mechanisms to account for this finding are not well characterized. Our preliminary data demonstrate that high-frequency blood donation is associated with severe reductions in iron stores, decreased oxidative stress, and improved vascular endothelial function when compared with sporadic donation. Since improved vascular endothelial function is known to be associated with decreased cardiovascular morbidity and mortality, these preliminary data support a potential mechanistic link between blood donation and reduced cardiovascular risk. We now propose a prospective interventional trial to investigate potential mechanisms linking blood donation and vascular endothelial function in voluntary blood donors. We hypothesize that serial phlebotomy is associated with improved vascular function related to physiological and biochemical effects of iron removal and blood removal. To test this hypothesis, 150 iron-replete voluntary blood donors currently deferred from active donation for non-medical reasons will be randomly assigned to 3 treatment groups: four 500 ml phlebotomy procedures over 6 months without replacement of lost iron, four 500 ml phlebotomy procedures over 6 months with intravenous replacement of lost iron, or sham phlebotomy. This 3-arm study design provides the means to distinguish the relative contributions of blood loss vs. iron loss on biological responses to serial phlebotomy. Flow-mediated dilation in the brachial artery (a non-invasive measure of vascular endothelial function) in the basal state and in response to transient hyperhomocysteinemia, serum and urinary measures of iron stores and oxidative stress, red cell and plasma volume, regional arterial wall shear stress, and erythropoietin levels will be obtained before and after the assigned study intervention. Mulitvariate mixed effects models will be used to determine the association between study treatment and vascular function and whether physiological and biochemical correlates of iron and blood removal are mediators of this association. This study will provide new insight into the relationship between iron stores and vascular function and will provide new data on the health effects of blood donation that could impact the nation's blood supply. More than 50% of all Americans will require a blood donation at least one time in their lives. We propose a prospective randomized double-blind study to determine the effects of blood donation on vascular function. The overall goal of the proposal is to better characterize the potential impact of blood donation on cardiovascular health. The findings of this study will provide novel data that could favorably impact the nation's blood supply, and could influence public policy decisions on screening for hemochromatosis (one of the most common genetic diseases in the US) and regulation of iron content in nutritional supplements and foods.